Hydrochloric Acid → 6-((8-Fluoro-6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline

HRID 219223Notes

Reaction equation

HRID 219223 reaction equation
Cl[C:2]1[CH:3]=[C:4]([F:22])[C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.ClC1C=C(F)C(NN)=NC=1.N1[C:42]2[C:37](=[CH:38][C:39](CC(OC)=O)=[CH:40][CH:41]=2)C=CC=1.Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:22][C:4]1[C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[CH:7]=[C:2]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:3]=1

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 62657Potassium Phosphate, TribasicHCID 66827Phenylboronic AcidHCID 1514202Methyl 6-quinolineacetateHCID 226196745-Chloro-3-fluoro-2-hydrazinylpyridineHCID 67502242Dicyclohexyl(2-(2,4,6-triisopropylcyclohexa-1,3-dienyl)phenyl)phosphineHCID 675042536-((6-Chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline2×

Product 1

HCID 441811466-((8-Fluoro-6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline. A mixture of 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine (500 mg, 3095 μmol) and methyl 2-(quinolin-6-yl)acetate (600 mg, 2982 μmol) in HCl (conc., 600 μL, 7200 μmol) was heat at 100° C. for 20 min. The mixture was then heated in a microwave at 180° C. for 40 min. The mixture was quenched with NaOH (5 N, 1.5 mL) and the suspension was filtered and washed with H2O. The resulting brown solid is mostly the desired product. The solid was then triturated with NaOH (5 N, 1 mL), filtered, and washed with H2O. LCMS (ESI pos. ion): calc'd for C16H10ClFN4: 312.0; found: 313.1 (M+1). 2) 6-((8-fluoro-6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline. A mixture of Pd(OAc)2 (6.46 mg, 28.8 μmol), potassium phosphate (367 mg, 1727 μmol), phenylboronic acid (211 mg, 1727 μmol), dicyclohexyl(2-(2,4,6-triisopropylcyclohexa-1,3-dienyl)phenyl)phosphine (27.6 mg, 57.6 μmol), and 6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline (180 mg, 576 μmol) in dioxane (6 mL)-H2O (2 mL) was heated to 100° C. under nitrogen for 20 h. The mixture was cooled to rt and partitioned between H2O and CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The residual was purified on silica using MeOH in DCM (0-5%) to give a pink solid. This solid was triturated with hexane-EtOAc-DCM (hot) to give a brown solid (105 mg). LCMS (ESI pos. ion): calc'd for C22H15FN4: 354.1; found: 355.2 (M+1).

Workup

  1. temperatureThe mixture was then heated in a microwave at 180° C. for 40 min
  2. customThe mixture was quenched with NaOH (5 N, 1.5 mL)
  3. filtrationthe suspension was filtered
  4. washwashed with H2O
  5. customThe solid was then triturated with NaOH (5 N, 1 mL)
  6. filtrationfiltered
  7. washwashed with H2O
  8. temperaturewas heated to 100° C. under nitrogen for 20 h
  9. temperatureThe mixture was cooled to rt
  10. custompartitioned between H2O and CH2Cl2
  11. dry with materialThe organic layer was dried over MgSO4
  12. concentrationconcentrated
  13. customThe residual was purified on silica
  14. customto give a pink solid
  15. customThis solid was triturated with hexane-EtOAc-DCM (hot)

Sources & evidence

ORD record
ord-24b203445499417391de93e37f1cf09d
Source dataset
uspto-grants-2012_06
Patent number
US08198448B2

Reaction notes

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